Here, we focused on epigenetic changes in leukemia and multiple myeloma (MM) cells. We show how the histone signature, DNA methylation, and levels of select tumor suppressor proteins can be affected by inhibitors of HDAC and Dnmts. Both inhibitors, Trichostatin A and 5-azacytidine, have ability to change histone signature by tumor-specific manner. In MM cells we observed changes in H3K4 methylation, while in leukemia cells, especially H3K9 methylation was affected by select inhibitors. Compared to normal peripheral blood lymphocytes, tumor cell samples were characterized by increased H3K9 acetylation, H3K4me2, H3K9me2, HP1a level and specific changes were also observed for DNA methylation. Additionally, we showed that the tumor suppressor pRb1 is more sensitive to epigenetic-based anti-cancer stimuli than p53. We have found significant decrease in the levels of pRb1 and p53 in both myeloma and leukemia cells after HDAC inhibition.